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Alkene Epoxidation Reagent, Lecture notes of Chemistry

Christian Theological Seminary (CTS)Chemistry

Prilezhaev Reaction, Hydroperoxides, general formula and mechanism

Typology: Lecture notes

2020/2021

Uploaded on 05/24/2021

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ekaksha 🇺🇸

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16
Alkene Epoxidations
• A huge topic which we will only skim the surface of
• References will be include for those who want more detail
Peracids: The Prilezhaev (Prileschajew) Reaction
Reagent:
Transformation:
General Mechanism
R O
O
OH
O
• for the Caddick group with
their love of named reactions
R'
RR" O
O
OH
O
O
O
H
R'
R
R"
R
R'O
R" O
O
H
Use in Synthesis
• Peracids much weaker acids than carboxylic acids (pKa 8.2 vs 4.8)
• But carboxylic acid is a by-product so buffer with NaHCO3
• Peracids are electrophilic so electron withdrawing groups on R good (mCPBA)
• Electron-rich alkenes more reactive
•Hydrogen-bonding can direct epoxidations
OH ArCO3HOH
O
Hydroperoxides
• H2O2 & alkyl hydroperoxides require the presence of a transition metal to initiate epoxidation
•tBuO2H (TBHP) favoured as safe, soluble and stable in anhydrous solvents and cheap
M O
O
R
+
M O
O
R
O M
O
R
M
O
O
R
OM OR+
H
O
H
O
O
Ar
OH
pf3
pf4
pf5
pf8
pf9
pfa

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Alkene Epoxidations

• A huge topic which we will only skim the surface of

• References will be include for those who want more detail

Peracids: The Prilezhaev (Prileschajew) Reaction

Reagent:

Transformation:

General Mechanism

R O
O
O
H
O

• for the Caddick group with

their love of named reactions

R'
R R"^ O
O
O
H
O
O
O
H
R'
R
R"
R
O R'
R" O
O
H

Use in Synthesis

• Peracids much weaker acids than carboxylic acids (pKa 8.2 vs 4.8)

• But carboxylic acid is a by-product so buffer with NaHCO 3

• Peracids are electrophilic so electron withdrawing groups on R good ( m CPBA)

• Electron-rich alkenes more reactive

• Hydrogen-bonding can direct epoxidations

OH

ArCO 3 H

OH
O

Hydroperoxides

• H 2 O 2 & alkyl hydroperoxides require the presence of a transition metal to initiate epoxidation

• t BuO 2 H (TBHP) favoured as safe, soluble and stable in anhydrous solvents and cheap

M O
O
R
M O
O
R
O M
O
R
M
O
O
R

O + M OR

H
O
H
O
O

Ar

O
H

Directed Epoxidations Utilising Hydroperoxides

93CR1307 (directed reactions)

  • The use of transition metals can allow directed epoxidations
    • Use to control chemoselectivity
  • Used to control stereoselectivity
OH O OH^ O OH

m CPBA: 1 : 2

TBHP / VO(acac) 2 49 : 1

Cl MeO

NH
O
O
O
HN

OMe

OH

TBHP

VO(acac) 2

Cl MeO

NH
O
O
O
HN

OMe

OH
O
  • chemo- and

stereoselective

Mechanism

  • TBHP rapid ligand exchange
  • activation of

peroxide

  • internal delivery
HO HO^ O

t BuOOH t BuOH

VO(acac) 2

O
O V O
O O
O
O V O
O O O^

t Bu

O V
O O
O O
O

t Bu

O V
O
O
O
O
O

t Bu

H

Use in Synthesis

  • DCM is an uniquely efficient solvent
  • Complex can not be stored
  • Catalyst must be aged
R^2 OH^
R^2 OH
R^3
OH
R^3
R^1
OH
R^3
R^1
R^2

Yield = good

e.e. = 90 %

few examples

but generally good

Substrates

OH
R^3

R^2 Poor

substrate

HO

Ti(O i Pr) 4 ,

(+)-DET, TBHP

HO
O HO
HO
H

TsOH

Kinetic resolution

R^2 R 1
R^3 OH
R
R
R^2 R 1
R^3 OH
H

"O" (–)-DET

slow fast

R^2 OH
R^1 R
R^3
R^2 OH
R^1 R
R^3
R^2 OH
R^1 R
R^3
O
  • R group hinders attack and

slows epoxidation down

  • produced faster
  • If allylic alcohol is the desired product use 0.6 equiv. TBHP
  • If epoxy alcohol is the desired product use 0.45 equiv. TBHP
  • must stop reaction before

100% completion or you will just

recover a different racemate

  • both enantiomers react just at

different rates

HO

OBn

BnO OH O

HO (^) OBn O (^) O

OBn

MeO 2 C

OBn

OH OTPS

OBn

OH OTPS
O

OBn

t BuOCO OH OH

BnO (+)-DET, Ti(OTBHP i Pr) 4 , OH OH OTBS

(-)-DET, Ti(O i Pr) 4 , TBHP (^) 1. Swern

  1. Wittig
1. DIBAL
  1. t BuCOCl
  2. TPSCl
  3. DIBAL
(-)-DET,

Ti(O i Pr) 4 , TBHP

  1. Red-Al
  2. t BuCOCl
  • Two building blocks from KC Nicolaou's synthesis of amphotericin B show the power of SAE

Dioxirane Epoxidations

Reagent:

Transformation:

General Mechanism

R R^1
O O
O
R
H
H
O
O
R
R
H
H
O
R

• syn -addition

• concerted

mechanism

• cis -spiro

transition state

Preparation

O H O^ O SO^3
O O^ SO 3
O
H
O
O

"SO 4 "

• Most common dioxirane is dimethyldioxirane (DMDO)

• Prepared as a pale yellow solution in acetone by the action of oxone or caroate KHSO 5

• ~0.08–0.10 M acetone solution "distilled" off with carrier gas to prevent further reaction of

oxone and DMDO

Use in Synthesis

• cis -alkenes react more efficiently for steric reasons (~7-9 times more reactive)

R
R
O
O
R
R
O
O

• Stereocentrol is a result of steric interactions

• Addition of DCM or H 2 O decreases stability therefore increases reactivity

• Used at low temperature and neutral conditions (as generates acetone as a by-product)

• Mild so can generate very sensitive epoxides

H

t Bu

O
O
H

O t Bu

84 % O

• Disadvantages: VERY reactive, heteroatoms and hydroxyl groups can be oxidised

• Disadvantages: Even unactivated C–H can be oxidised

2–

Jacobsen–Katsuki Epoxidation

Reagent:

Transformation:

General Mechanism

O
N N
O O
R^3 R^3
R^2 R^2 R 1
R^1

Mn

  • Still contraversial

97Ang

•Possibilities

M
O
R R^1
M
O
R R^1
M
O
R
R^1

concerted stepwise

(radical or polar)

oxametallocycle

  • oxidations proceed with a degree of scrambling of geometry t Bu Et

Ph CO 2 Et

TMS

> 99 : 1 cis : trans epoxide

78 : 22 cis : trans epoxide

29 : 71 cis : trans epoxide

  • Suggests that concerted mechanism is not occurring
  • Present believe is probably radical - stepwise mechanism (00Ang589)

NaOCl

(bleach)

  • Aim to develop an asymmetric epoxidation catalyst which would operate on substrates with no

functionality for preco-ordination

  • A number of reasonably efficient porphyrin based oxo–transfer reagents were developed but

the real success story has been the us of SALEN–based reagents

Stereoselectivity

  • My interpretation would again suggest that Katsuki and Jacobsen disagree on this
  • Both agree that alkene approaches metal oxo complexes side-on

M

O
R R^1

M

O
R
R^1

M

O
R
R^1
  • approach so that π-HOMO

of alkene overlaps with

π*-LUMO of oxo

  • cis alkenes work well
  • trans alkenes generally bad

OMnN N

t Bu

O

t Bu

t Bu

t Bu (^) H

O H
RLARGE
RSMALL
N N
O O

t Bu

t Bu

t Bu

t Bu

H H

Mn

RS RL
  • Jacobsen implies attack on oxo-species occurs from the back face over the diamine bidge
  • Katsuki implies that skewed shape of salen complex results in attack from the side
    • small substituent

passes axial proton

  • bulky t Bu groups block

attack from front or sides

O

N (^) Mn N H O

O H
  • bulky t Bu groups block

approach from front

  • skewed shape of salen

complex shields one side

of nucleophile

  • back face blocked by H

of cyclohexane group

RL
RS
RL
RS
  • large substituent far

from bulky front face